The genetic background for the onset of cancer are proto-oncogenes and oncogenes. Proto-oncogenes are normal genes of the cell which have the potential of becoming oncogenes. All oncogenes code for and function through a protein. In the majority of cases they have been shown to be components of signal transduction pathways. Oncogenes arise in nature from proto-oncogenes through point mutations or translocations, thereby resulting in a transformed state of the cell harbouring the mutation. Cancer develops through a multi-step process involving several mutational events and oncogenes. In its simplest form a single base substitution in a proto-oncogene may cause the resulting gene product to differ in one amino acid.
In experimental models involving murine tumours it has been shown that point mutations in intracellular "self"-proteins may give rise to tumour rejection antigens, consisting of peptides differing in a single amino acid from the normal peptide. The T cells recognizing these peptides in the context of the major histocompatibility (MHC) molecules on the surface of the tumour cells are capable of killing the tumour cells and thus rejecting the tumour from the host. (Boon, T. et al, Cell, 1989, Vol. 58, p 293-303)
In the field of human cancer immunology the last two decades has seen intensive efforts to characterize genuine cancer specific antigens.
In particular, effort has been devoted to the analyses of antibodies to human tumour antigens. The prior art suggests that such antibodies could be used both for diagnostic and therapeutical purposes, for instance in connection with an anti-cancer agent. One problem is that antibodies can only bind to tumour antigens that are exposed on the surface of tumour cells. For this reason the efforts to produce a cancer treatment based on the immune system of the body has been less successful than expected.
Antibodies typically recognize free antigen in native conformation and can potentially recognize almost any site exposed on the antigen surface. In contrast to the antibodies produced by the B cells, T cells recognize antigens only in the context of MHC molecules, designated HLA (human leucocyte antigen) in humans, and only after appropriate antigen processing, usually consisting of proteolytic fragmentation of the protein, resulting in peptides that fit into the groove of the MHC molecules. This enables T cells to recognize also peptides derived from intracellular proteins. T cells can thus recognize aberrant peptides derived from anywhere in the tumor cell, in the context of MHC molecules on the surface of the tumor cell, and subsequently can be activated to eliminate the tumor cell harbouring the aberrant peptide.
The HLA molecules are encoded by the HLA region on the human chromosome No 6. The class I molecules are encoded by the HLA A, B and C subloci, and the class II molecules are encoded by the DR, DP and DQ subloci. All the gene products are highly polymorphic. Different individuals thus express distinct HLA molecules that differ from those of other individuals. This is the basis for the difficulties in finding HLA matched organ donors in transplantations. The significance of the genetic variation of the HLA molecules in immunobiology is reflected by their role as immune-response genes. Through their peptide binding capacity, the presence or absence of certain HLA molecules governs the capacity of an individual to respond to peptide epitopes. As a consequence, HLA molecules determine resistance or susceptibility to disease.
T cells may control the development and growth of cancer by a variety of mechanisms. Cytotoxic T cells, both HLA class I restricted CD8+ and HLA Class II restricted CD4+, may directly kill tumour cells carrying the appropriate tumour antigens. CD4+ helper T cells are needed for cytotoxic T cell responses as well as for antibody responses, and for inducing macrophage and LAK cell killing.
Although the prior art has identified many oncogenes and their protein products, and a recently published study has shown that the T cell repertoire of a healthy person includes T cells with a specificity against a synthetic peptide fragment derived from one p21 ras oncogene product, no previous studies have defined the correct antigens or antigenic sites giving rise to tumour specific T cell immunity.
Thus the present invention is based on the idea that another possible approach for combatting cancer is by using the body's own immune system through an activation and strengthening of the immune response from specific T cells.